EP0526495A1 - 1,5-benzothiazepinone derivatives, their preparations and pharmaceutical use - Google Patents

1,5-benzothiazepinone derivatives, their preparations and pharmaceutical use

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Publication number
EP0526495A1
EP0526495A1 EP91907834A EP91907834A EP0526495A1 EP 0526495 A1 EP0526495 A1 EP 0526495A1 EP 91907834 A EP91907834 A EP 91907834A EP 91907834 A EP91907834 A EP 91907834A EP 0526495 A1 EP0526495 A1 EP 0526495A1
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Prior art keywords
compounds
formula
cis
methoxyphenyl
dihydro
Prior art date
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EP91907834A
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German (de)
French (fr)
Inventor
Aldo Salimbeni
Saturnino Caliari
Francesco Fici
Elso Manghisi
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Istituto Luso Farmaco dItalia SpA
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Istituto Luso Farmaco dItalia SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention concerns diltiazem analogues, a process for their preparation and pharmaceutical compositions containing them.
  • Diltiazem disclosed in US 3562257, is a 1,5-ben- zothiazepinone derivative which, thanks to its calcium- antagonistic properties, is used in various cardiovascular pathologies such as hypertension and ischemic cardiopathy.
  • the pharmacolcinetics of diltiazem in humans is however characterized by a short elimination half-life whereby the drug must be administered every 4-6 hours, with problems of patient's compliance and with very inconstant plasma concentrations.
  • 1,5-benzothiazepinone derivatives of general formula I characterized by the presence on the basic nitrogen of at least a branched or cyclic alkyl group and/or by a substitution in the alkyl chain, are endowed with a longer duration of action in comparison with diltiazem, together with similar or higher calcium antagonistic properties.
  • R is hydrogen or an R 5 CO group wherein R 5 is a C 1 -C 4 linear or branched alkyl or a phenyl group, optionally substituted by halogen atoms, methoxy or nitro groups; R 1 and R 2 , which are the same or different, are a C 1 -C 4 .
  • R 3 is a C 1 -C 4 linear or branched alkyl
  • R 4 is hydrogen, chlorine, methoxy
  • n is 1 or 2
  • m is zero or 1 with the proviso that when m is zero, at least one of R 1 and R 2 is a branched alkyl group or a cycloalkyl group.
  • the invention concerns also the diastereoisomers, the enantiomers or mixtures thereof of the compounds of formula I.
  • the groups in positions 2 and 3 are in cis position and their configuration is 2S, 3S.
  • Said US 3562257 discloses compounds of formula I wherein m is zero and R 1 and R 2 are the same and represent lower alkyl groups. All the examples refer to compounds wherein R 1 and R 2 are methyl.
  • the invention concern also the salts of the compounds I with pharmaceutically acceptable inorganic acids such as hydrochloric, hydrobromic, nitric, sulfunic, phosphoric acid and the like, as well as with pharmaceutically acceptable organic acids such as acetic, propionic, maleic, fumaric, malic, oxalic, tartaric, nitric, methansulfonic acid and the like.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, hydrobromic, nitric, sulfunic, phosphoric acid and the like
  • pharmaceutically acceptable organic acids such as acetic, propionic, maleic, fumaric, malic, oxalic, tartaric, nitric, methansulfonic acid and the like.
  • Particularly preferred compounds I are those wherein:
  • R 1 or R 2 is isopropyl, t- butyl, cyclopropyl, cyclohexyl and the other is methyl or isopropyl;
  • R 3 is hydrogen and R 1 and R 2 are as above defined.
  • Particularly preferred compounds are those wherein R 4 is hydrogen and R is acetyl.
  • C 3 -C 7 cycloalkyl residues are cyclopropyl, cyclopentyl, cyclohexyl.
  • R 5 has the above defined meanings.
  • the compounds of formula I wherein R is a R 5 CO group wherein R 5 is as above defined may be prepared by reacting a compound of formula V
  • n, R 1 , R 2 , R 3 , R 4 are as above defined and Z is chlorine, bromine or a tosyloxy group.
  • the intermediates of formula V may be prepared from the corresponding compounds of formula II by reaction with the compounds of formula VII
  • X is chlorine, bromine and m, n, Z and R 3 have the above defined meanings.
  • condensation of the compounds of formula II with a compound of formula III is usually carried out in a solvent in the presence of an alkaline agent such as KOH, NaOH, K 2 CO 3 , NaH.
  • salts of formula III are hydrochloride, hydrobromide and the like.
  • the solvents may be selected from aliphatic ketones (acetone, methylethylketone etc), ethylacetate, di- methylsulfoxide, dimethylformamide, acetonitrile, te- trahydrofuran and dioxane.
  • the reaction is carried out at a temperature from 0° to 100oC, particularly from 20 to 70°C.
  • the condensation of a compound of formula I wherein R is hydrogen with a compound of formula IV or with an active derivative thereof may be carried out in a solvent in the presence or in the absence of an acidity acceptor.
  • An active derivative of compounds IV may be an anhydride (e.g. acetic, propionic) or a chloride (acetyl chloride, propionyl chloride and the like).
  • Pyridine, triethylamine, N-methylmorpholine and the like may be used as acidity acceptors whereas suitable solvents are acetic acid, chloroform, methylene chloride, dimethylformamide, tetrahydrofuran.
  • the reaction temperature ranges from 20 to 140oC.
  • the reaction for the preparation of compounds V may be carried out in an apolar or polar solvent such as methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, dimethylsulfoxide.
  • apolar or polar solvent such as methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, dimethylsulfoxide.
  • the reaction temperature ranges form 0° to 150oC according to the boiling temperature of the solvent.
  • the compounds of formula I and their pharmaceutically acceptable salts have advantageous calcium antagonistic properties.
  • the p IC 50 and p A 2 values of several compounds of the invention are higher than 7. ln vivo the compounds of formula I turned out to have remarkable and long-lasting anti-anginal properties as it was shown by the vasopressine-induced angina in the rat (according to the method of M.Leitold, H.Laufen, Arzneim. Forsch. 33, 1117 (1983)). Several compounds have DE 50 's comparable to that of diltiazem but with a longer duration. In pharmacokinetic studies carried out in the conscious incannulated rat, several compounds show an elimination t 1/2 after oral administration higher than that of diltiazem. The compounds I are also endowed with a favourable and long-lasting antihypertensive activity in the spontaneously hypertensive rat (SHR) test.
  • SHR spontaneously hypertensive rat
  • the compounds I or their pharmaceutically acceptable salts may be used in form of pharmaceutical compositions suitable for the oral or parenteral administration.
  • compositions may be in solid form such as tablets, pills, capsules or suppositories or in liquid forms such as solutions, suspensions or emulsions.
  • the pharmaceutical preparations may be in form of sterile solutions.
  • the compounds I will be usually administered in unit doses ranging form 1 to 100 mg to patients affec ted by cardiovascular pathologies such as arrythmias, hypertension, i schemic cardiopathy.
  • Example 1 (a) The raw material (obtained ad disclosed in Example 1 (a)), was dissolved in 15 ml anhydrous pyridine and treated with 0.23 g pivaloyl chloride. After 24 hours, the reaction mixture was poured in water and extracted with CH 2 Cl 2 . The organic phases were collected and evaporated to drynes ⁇ . 0.9 g residue were converted to the corresponding maleic acid salt; m.p. 128-130°C (acetone-isopropyl ether).

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  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

On décrit des composés répondant à la formule générale (I) et leurs sels pharmaceutiquement acceptables, des procédés de préparation de ces composés et des compositions pharmaceutiques les contenant. Les nouveaux composés, caractérisés par la présence sur l'azote basique d'au moins un groupe alkyle cyclique ou ramifié et/ou par une substitution effectuée dans la chaîne alkyle, sont dotés d'excellentes propriétés antagonistes du calcium et d'une action résiduelle plus longue que celle du diltiazem. Lesdits composés sont utiles au traitement de plusieurs pathologies vasculaires telles que l'hypertension et la cardiopathie ischémique.Compounds corresponding to general formula (I) and their pharmaceutically acceptable salts, processes for the preparation of these compounds and pharmaceutical compositions containing them are described. The new compounds, characterized by the presence on basic nitrogen of at least one cyclic or branched alkyl group and / or by a substitution carried out in the alkyl chain, have excellent calcium antagonistic properties and a residual action longer than that of diltiazem. Said compounds are useful for the treatment of several vascular pathologies such as hypertension and ischemic heart disease.

Description

1,5-BENZOTHIAZEPINONE DERIVATIVES. THEIR PREPARATIONS AND PHARMACEUTICAL USE
The present invention concerns diltiazem analogues, a process for their preparation and pharmaceutical compositions containing them.
Diltiazem, disclosed in US 3562257, is a 1,5-ben- zothiazepinone derivative which, thanks to its calcium- antagonistic properties, is used in various cardiovascular pathologies such as hypertension and ischemic cardiopathy. The pharmacolcinetics of diltiazem in humans is however characterized by a short elimination half-life whereby the drug must be administered every 4-6 hours, with problems of patient's compliance and with very inconstant plasma concentrations.
It has new been surprisingly found that 1,5-benzothiazepinone derivatives of general formula I, characterized by the presence on the basic nitrogen of at least a branched or cyclic alkyl group and/or by a substitution in the alkyl chain, are endowed with a longer duration of action in comparison with diltiazem, together with similar or higher calcium antagonistic properties.
The compounds of the invention have the following formula: wherein R is hydrogen or an R5CO group wherein R5 is a C1-C4 linear or branched alkyl or a phenyl group, optionally substituted by halogen atoms, methoxy or nitro groups; R1 and R2, which are the same or different, are a C1-C4. linear or branched alkyl or a C3-C7 cycloalkyl; R3 is a C1-C4 linear or branched alkyl; R4 is hydrogen, chlorine, methoxy; n is 1 or 2; m is zero or 1 with the proviso that when m is zero, at least one of R1 and R2 is a branched alkyl group or a cycloalkyl group.
The invention concerns also the diastereoisomers, the enantiomers or mixtures thereof of the compounds of formula I.
The groups in positions 2 and 3 are in cis position and their configuration is 2S, 3S.
Said US 3562257 discloses compounds of formula I wherein m is zero and R1 and R2 are the same and represent lower alkyl groups. All the examples refer to compounds wherein R1 and R2 are methyl.
Other analogues of diltiazem are disclosed in GB 2143532, EP 256888 and WO 8912633.
The invention concern also the salts of the compounds I with pharmaceutically acceptable inorganic acids such as hydrochloric, hydrobromic, nitric, sulfunic, phosphoric acid and the like, as well as with pharmaceutically acceptable organic acids such as acetic, propionic, maleic, fumaric, malic, oxalic, tartaric, nitric, methansulfonic acid and the like.
Particularly preferred compounds I are those wherein:
- m is zero, n is 1, one of R1 or R2 is isopropyl, t- butyl, cyclopropyl, cyclohexyl and the other is methyl or isopropyl;
- m is 1, n is 1, R3 is methyl and R1 and R2 are as above defined;
- m is 1, n is 1, R3 is hydrogen and R1 and R2 are as above defined.
Particularly preferred compounds are those wherein R4 is hydrogen and R is acetyl.
Examples of C3-C7 cycloalkyl residues are cyclopropyl, cyclopentyl, cyclohexyl.
The compounds of the inventions wherein R is hydrogen or a R5CO group wherein R5is as above defined, are prepared by reacting a benzothiazepinone derivative of formula II
with a compound of formula III
wherein m, n, R1, R2, R3, R4 are as above defined and X is halogen.
The so obtained compounds of formula I wherein R is H may be transformed in the compounds I wherein R is R5CO by reaction with compounds of formula IV or their reactive derivatives
R5---COOH (IV)
wherein R5 has the above defined meanings.
Alternatively, the compounds of formula I wherein R is a R5CO group wherein R5 is as above defined, may be prepared by reacting a compound of formula V
wherein m, n, R1, R2, R3, R4 are as above defined and Z is chlorine, bromine or a tosyloxy group.
The intermediates of formula V may be prepared from the corresponding compounds of formula II by reaction with the compounds of formula VII
wherein X is chlorine, bromine and m, n, Z and R3 have the above defined meanings.
The condensation of the compounds of formula II with a compound of formula III (optionally salified) is usually carried out in a solvent in the presence of an alkaline agent such as KOH, NaOH, K2CO3, NaH.
Examples of salts of formula III are hydrochloride, hydrobromide and the like.
The solvents may be selected from aliphatic ketones (acetone, methylethylketone etc), ethylacetate, di- methylsulfoxide, dimethylformamide, acetonitrile, te- trahydrofuran and dioxane.
The reaction is carried out at a temperature from 0° to 100ºC, particularly from 20 to 70°C. The condensation of a compound of formula I wherein R is hydrogen with a compound of formula IV or with an active derivative thereof may be carried out in a solvent in the presence or in the absence of an acidity acceptor. An active derivative of compounds IV may be an anhydride (e.g. acetic, propionic) or a chloride (acetyl chloride, propionyl chloride and the like). Pyridine, triethylamine, N-methylmorpholine and the like may be used as acidity acceptors whereas suitable solvents are acetic acid, chloroform, methylene chloride, dimethylformamide, tetrahydrofuran. The reaction temperature ranges from 20 to 140ºC.
The reaction for the preparation of compounds V may be carried out in an apolar or polar solvent such as methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, dimethylsulfoxide.
The reaction temperature ranges form 0° to 150ºC according to the boiling temperature of the solvent.
In order to neutralize the organic or inorganic acid HX released from the reaction, it is either possible to use an excess of the base VI or an inorganic base such as potassium or sodium carbonate.
Whenever the above reactions yield mixtures of diastereoisomers, these may be separated by usual methods (fractional crystallization, chromatography).
The compounds of formula I and their pharmaceutically acceptable salts have advantageous calcium antagonistic properties.
These properties were studied in vitro by displacement of 3H-diltiazem from its binding sites in the cardiac tissue (according to the method of H.Glossmann et al., FEBS 160, 226 (1983) or by the inhibition of the tonic contraction induced in the rabbit isolated atrium (according to the method of M.Spedding, Arch. Pharmacol. 318, 234 (1982)).
The p IC50 and p A2 values of several compounds of the invention are higher than 7. ln vivo the compounds of formula I turned out to have remarkable and long-lasting anti-anginal properties as it was shown by the vasopressine-induced angina in the rat (according to the method of M.Leitold, H.Laufen, Arzneim. Forsch. 33, 1117 (1983)). Several compounds have DE50's comparable to that of diltiazem but with a longer duration. In pharmacokinetic studies carried out in the conscious incannulated rat, several compounds show an elimination t 1/2 after oral administration higher than that of diltiazem. The compounds I are also endowed with a favourable and long-lasting antihypertensive activity in the spontaneously hypertensive rat (SHR) test.
As an example, the biological properties of the compounds cis (+)-3-acetyloxy-2,3-dihydro-3-[2-(N-iso- propyl-N-methylaminoethyl]-2-(4-methoxyphenyl)-1,5-ben- zothiazepin-4(5H)-one (Compound A) (Example 1) and of cis (+)-3-acetyloxy-2,3-dihydro-5-(2-methy1-3-dimethyla- minopropyl)-2(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one (Compound B) (diastereoisomer B, Example 3) in comparison with diltiazem. recepto- rabbit angina pharmaco- rial isolated vasopres- kinetics binding atrium sine test in the rat (pIC50) (pA2) rat (iv) (50 mg/kg/os)
ED50 duration
(mg/kg) (min) t 1/2 (min)
Compound A 7.19 7.30 0.49 78 92
Compound B 7.52 7.20 0.54 72 71
Diltiazem 7.10 7.35 0.45 54 57
The compounds I or their pharmaceutically acceptable salts may be used in form of pharmaceutical compositions suitable for the oral or parenteral administration.
Usual excipients such as starch, lactose, glucose, arabic gum, stearic acid etc may be used. The pharmaceutical compositions may be in solid form such as tablets, pills, capsules or suppositories or in liquid forms such as solutions, suspensions or emulsions.
Moreover, if administered parenterally, the pharmaceutical preparations may be in form of sterile solutions.
The compounds I will be usually administered in unit doses ranging form 1 to 100 mg to patients affec ted by cardiovascular pathologies such as arrythmias, hypertension, i schemic cardiopathy.
The following examples further illustrate the invention.
The melting points are not correct, the identity of the compounds and their purity has been evaluated by elemental analysis (C,H,N) and IR, UV, NMR and mass spectrometry.
EXAMPLE 1
Cis(+)-3-acetyloxy-2,3-dihydro-5-(2-N-isopropyl-N- methylaminoethyl)-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4(5H)-one hydrobromide
(a) A mixture of cis(+)-2,3-dihydro-3-hydroxy-2-(4- methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one (3.3 g), N- isopropyl-N-methylaminoethyl chloride hydrochloride (1.5 g) and K2CO3 (1.5 g) was suspended in 30 ml methyl ethyl ketone and refluxed for 12 hours. The residue was treated with ethyl ether and diluted with HCl (1:1). The organic phase was separated. The acid aqueous phase was alkalinized with 10% NaOH and extracted several times with ethyl ether. The organic phases were pooled and evaporated to dryness. The oily residue (3.1 g) was directly used for the subsequent reaction.
(b) The product obtained in (a) was dissolved in 31 ml acetic anhydride and let to stand for 12 hours. The acetic anhydride was distilled off under vacuum. The residue was dissolved in 32 ml ethyl ether and treated with a 6N HBr solution in isopropyl alcohol to acid pH. The precipitate was separated by filtration and crystallised from acetone-ethyl ether. 2.4 g white solid were cbtained; m.p. 137-140ºC. The following compounds were prepared according to the above procedure.
- cis (+)-3-acetyloxy-5-(2-N-ethyl-N-methylaminoethyl)- 2 , 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one oxalate monohydrate; m.p. 105-108°C (ethyl acetate);
cis (+)-3-acetyloxy-5-(2-N-t-butyl-N-methylaminoe- thyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4 (5H)-one oxalate; m.p. 86-89°C (isopropyl alcohol- ethyl ether);
- cis (+)-3-acetyloxy-5-(2-N-cyclopropyl-N-methylamino- ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4(5H)-one;
cis (+)-3-acetyloxy-5-(2-N-cyclohexyl-N-methylamino- ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4 (5H)-one;
- cis (+)-3-acetyloxy-5-(2-N-diisopropyl-N-methylamino- ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4(5H)-one oxalate; m.p. 86-89ºC (isopropyl alcohol- ethyl-ether).
EXAMPLE 2
Cis(+)-3-acetyloxy-2,3-dihydro-5-(2-methyl-3-dimethyla- minopropyl)-2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one oxalate (diastereoisomer A)
(a) cis (+)-3-acetyloxy-5-(3-chloro-2-methylpropyl)- 2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one.
5 g cis (+)-3-acetyloxy-2,3-dihydro-2-(4-methoxy- phenyl)-1,5-benzothiazepin-4(5H)-one were dissolved in 30 ml dimethyIformamide, cooled at -7ºC. 1.4 g 88% KOH and, after 10 minutes, 3.8 g 1-bromo-3-chloro-2- methyIpropane were slowly added. The temperature was then raised to 0°C and the mixture was stirred for 4 hours. The reaction mixture was then poured in 250 ml 0.6N NH4Cl solution and extracted with CH2Cl2. The collected organic phases were washed with H2O, dried on Na2SO4 and evaporated under reduced pressure. 6 g a thick orange oil were obtained and were dissolved in hot isopropyl alcohol. A crystalline solid precipitated by cooling, m.p. 100-103ºC.
The following compounds were prepared according the above procedure:
- cis (+)-3-acetyloxy-5-(3-chloro-2-ethylpropyl)-2,3-di- hydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one; - cis (+)-3-acetyloxy-5-(3-chloro-2-isopropyl)-2,3-dihy- dro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one.
(b) 5 g chloro derivative, obtained as in (a), were dissolved in 30 ml dimethylformamide; 10 g dimethy- lamine and 0.05 g KI were added to the solution. The solution was then heated to 80ºC for 4 hours. The reaction mixture was then poured in 300 ml H2O and the separated solid was extracted with ethyl ether. The organic phase was evaporated to dryness and the residue was reacted with 35 ml acetic anhydride at room temperature. After 48 hours the excess acetic anhydride was eliminated and the residue was treated with ethyl ether. The white solid was separated and salified with oxalic acid in isopropyl alcohol. 3.5 g product, which were purified by isopropyl alcohol crystallization, were obtained; m.p. 177-179ºC. [α]D 20=148 (H2O).
The following compounds were prepared according the above procedure: - cis(+)-3-acetyloxy-2,3-dihydro-5-[2-methyl-3-(N-cy- clopropyl-N-methylamino)propyl]-2-(4-methoxyphenyl)- 1,5-benzothiazepin-4(5H)-one;
- cis(+)-3-acetyloxy-2,3-dihydro-5-[2-methyl-3-(N-cy- clohexyl-N-methylamino)propyl]-2-(4-methoxyphenyl)-1,5- benzothiazepin-4(5H)-one;
- cis(+)-3-acetyloxy-2,3-dihydro-5-[2-methyl-3-(N-di- methylamino)propyl]-2-(4-methoxyphenyl)-1,5-benzothia- zepin-4(5H)-one.
EXAMPLE 3
Cis (+)-3-acetyloxy-2,3-dihydro-5-(2-methyl-3-dimethyla- minopropyl)-2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one oxalate (diastereoisomer B)
5 g cis(+)-2,3-dihydro-3-hydroxy-2-(4-methoxyphe- nyl)-1,5-benzothiazepin-4(5H)-one, 2.9 g 2-methyl-3-di- methylaminopropylchloride hydrochloride, 5.7 g K2CO3, 1.4 ml H2O were reacted in 75 ml acetone, according to the procedure as in Example 1 (a), then reacted with 70 ml acetic anhydride, (see Example 1 (b)). The crude was treated with ethyl ether and the so obtained solid is filtered off and the solution was evaporated to dryness. This procedure was repeated. 4.3 g residue were dissolved in isopropyl alcohol and treated with 1.2 g oxalic acid. A solid, which was crystallized from acetone-ethyl ether, was obtained; m.p. 84-89°C; [α]D 20=+119.3 (H2O).
The following compounds was prepared according the above procedure:
- cis(+)-3-acetyloxy-7-chloro-2,3-dihydro-5-(2-methyl- 3-dimethylaminopropyl)-2-(4-methoxyphenyl)-1,5-ben- zothiazepin-4(5H)-one (starting from cis (+)-2,3-dihy- dro-7-chloro-3-hydroxy-2-(4-methoxyphenyl)-1,5-ben- zothiazepin-4(5H)-one).
EXAMPLE 4
Cis (+)-2,3-dihydro-5-(2-N-isopropyl-N-methylamino- ethyl)-3-(2,2-dimethylpropanoyloxy)-2-(4-methoxyphe- nyl)-1,5-benzothiazepin-4(5H)-one and pharmaceutically acceptable salts thereof
The raw material (obtained ad disclosed in Example 1 (a)), was dissolved in 15 ml anhydrous pyridine and treated with 0.23 g pivaloyl chloride. After 24 hours, the reaction mixture was poured in water and extracted with CH2Cl2. The organic phases were collected and evaporated to drynesε. 0.9 g residue were converted to the corresponding maleic acid salt; m.p. 128-130°C (acetone-isopropyl ether).

Claims

1. Compounds of general formula I and their diastere- oisomers or enantiomers or mixtures thereof
wherein R is hydrogen or an R5CO group wherein R5 is a C1-C4 linear or branched alkyl or a phenyl group, optionally substituted by halogen atoms, methoxy or nitro groups; R1 and R2, which are the same or different, are a C1-C4 linear or branched alkyl or a C3-C7 cycloalkyl; R3 is a C1-C4 linear or branched alkyl; R4 is hydrogen, chlorine, methoxy; n is 1 or 2; m is zero or 1 with the proviso that when m is zero, at least one of R1 and R2 is a branched alkyl group or a cycloalkyl group.
2. A compound according to claim 1 which is cis(+)-3- acetyloxy-2,3-dihydro-5-(2-N-isopropyl-N-methylamino- ethyl)-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)- one and their pharmaceutically acceptable salts.
3. A compound according to claim 1 which is cis(+)-3- acetyloxy-2,3-dihydro-5-(2-methyl-3-dimethylamino- propyl)-2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)- one and their pharmaceutically acceptable salts.
4. Process for the preparation of compounds of general formula I consisting in the reaction of
a benzothiazepinone derivative of formula II
with a compound of formula III
wherein m, n, R1, R2, R3, R4 are defined as in claim 1 and X is halogen.
5. A process for the preparation of compounds of general formula I consisting in the reaction of a compound of formula V
with- an amine of formula VI
(VI)
wherein m, n, R1, R2, R3, R4 are defined as in claim 1 and Z is chlorine, bromine or a tosyloxy group.
6. Pharmaceutical compositions comprising as an active principle an effective quantity of a compound according to claims 1-3 together with a suitable pharma ceutical excipient.
7. Use of a compound according to claims 1-3 for the preparation of a medicament to be used in cardiovascular pathologies.
EP91907834A 1990-04-27 1991-04-18 1,5-benzothiazepinone derivatives, their preparations and pharmaceutical use Withdrawn EP0526495A1 (en)

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IT20160A IT1240686B (en) 1990-04-27 1990-04-27 1,5-BENZOTHIAZEPINONIC DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL USE
IT2016090 1990-04-27

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CN (1) CN1056101A (en)
AU (1) AU645317B2 (en)
BG (1) BG97014A (en)
BR (1) BR9106372A (en)
CA (1) CA2081204A1 (en)
CS (1) CS120991A2 (en)
FI (1) FI924756A0 (en)
HU (1) HU9203326D0 (en)
IE (1) IE71033B1 (en)
IL (1) IL97859A0 (en)
IN (1) IN172160B (en)
IT (1) IT1240686B (en)
MA (1) MA22143A1 (en)
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DK0702009T3 (en) * 1994-09-16 1999-02-01 Orion Corp Fermion Process for the preparation of pharmaceutically active benzothiazepine derivatives
US5559229A (en) * 1995-06-01 1996-09-24 Acic (Canada) Inc. Method for the manufacture of benzothiazepine
WO1996038429A1 (en) * 1995-06-01 1996-12-05 Acic (Canada) Inc. Method for the manufacture of benzothiazepine derivatives
WO2006079077A2 (en) * 2005-01-20 2006-07-27 Acadia Pharmaceuticals Inc. Use of diltiazem or analogs thereof as modulators of ghrelin receptor

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US3562257A (en) * 1967-10-28 1971-02-09 Tanabe Seiyaku Co Benzothiazepine derivatives
IT1206505B (en) * 1983-07-22 1989-04-27 Schiapparelli Farma NEW BENZOTHIAZEPINONIC DERIVATIVES, METHOD FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT.
EP0256888B1 (en) * 1986-08-20 1991-07-03 McNeilab, Inc. Benzothiazepine vasodilators having aralkyl substitution
US4902684A (en) * 1988-06-20 1990-02-20 E. R. Squibb & Sons, Inc. Benzazepine and benzothiazepine derivatives
US4902687A (en) * 1989-03-27 1990-02-20 Eli Lilly And Company Excitatory amino acid receptor antagonists
ES2069003T3 (en) * 1989-04-28 1995-05-01 Tanabe Seiyaku Co PROCEDURE FOR PREPARING 1,5-BENZOTIAZEPINE DERIVATIVES.
JPH085869B2 (en) * 1990-03-08 1996-01-24 田辺製薬株式会社 Process for producing 1,5-benzothiazepine derivative

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Title
See references of WO9117153A1 *

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MA22143A1 (en) 1991-12-31
FI924756A (en) 1992-10-20
IT9020160A0 (en) 1990-04-27
IE71033B1 (en) 1997-01-15
RO111269B1 (en) 1996-08-30
IT1240686B (en) 1993-12-17
BR9106372A (en) 1993-04-27
BG97014A (en) 1993-12-24
AU645317B2 (en) 1994-01-13
FI924756A0 (en) 1992-10-20
PT97508A (en) 1992-01-31
CN1056101A (en) 1991-11-13
CA2081204A1 (en) 1991-10-28
IE911411A1 (en) 1991-11-06
JPH05506654A (en) 1993-09-30
ZA913171B (en) 1992-02-26
HU9203326D0 (en) 1993-01-28
IN172160B (en) 1993-04-17
IT9020160A1 (en) 1991-10-27
WO1991017153A1 (en) 1991-11-14
CS120991A2 (en) 1991-12-17
US5571807A (en) 1996-11-05
AU7695491A (en) 1991-11-27
IL97859A0 (en) 1992-06-21

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